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CML: Pros and Cons for Initial Therapy

NEW YORK—Multiple trials using second-generation tyrosine kinase inhibitors (TKIs) compared with imatinib have shown faster responses, lower rates of short-term disease progression, and deeper overall molecular response rates. Does that mean they should be the choice for initial therapy for patients in chronic-phase chronic myelogenous leukemia?

Not necessarily, said Charles Schiffer, MD, Professor of Medicine and Oncology and Interim Chair of the Department of Oncology at Karmanos Cancer Institute in Detroit.

In a presentation here at the International Congress on Hematologic Malignancies, Schiffer said clinicians must consider the longer-term toxicities recently described with second-generation TKIs. Furthermore, those trials have shown no differences in survival, he noted, citing the four-year follow-up results of the DASISION trial reported at last year's American Society of Hematology Annual Meeting by Jorge Cortes et al (Abstract 653).

“'Faster and deeper' is the ‘soft-porn mantra’ of CML that hematologists are hearing from drug reps, and will hear more of when imatinib goes off patent,” Schiffer said. “Because responses with second-generation TKIs are faster and deeper, the implication is that all patients should receive a second-generation TKI, with the conjecture that a higher percentage of patients could stop therapy with TKIs. But this is totally speculative and hypothetical.”

Schiffer cited the STIM (Stop Imatinib) trial, also reported at last year's ASH Annual Meeting by Francois-Xavier Mahon et al (Abstract 603), which concluded that imatinib can be safely discontinued in patients with a complete molecular response (CMR) of at least two years duration. But a very high fraction of STIM patients in CMR with high SOKOL scores quickly relapsed within six months after discontinuation, Schiffer pointed out.

“The disease comes back, and it comes back remarkably quickly.”

Conclusions from even large clinical trials cannot be applied with precision to individual patients. Schiffer said he was very comfortable starting treatment for his patients with 400 mg of imatinib, except in those with higher Sokol relative-risk scores, in whom he uses second-generation TKIs.

Adverse Effects

The choice then depends on potential toxicity issues in individual patients, he said. Known adverse events associated with long-term imatinib use include many low-grade chronic adverse events.

Adverse events for the second-generation TKIs are more serious: For dasatinib these include late pleural effusions and pulmonary hypertension; for nilotinib, hyperglycemia, peripheral arterial occlusive disease, and other arterial thromboses.

“Dasatinib is a safe drug, except when it isn't,” he said, advising clinicians to pay attention to patients on long-term dasatinib coming in with cardiopulmonary symptoms or respiratory problems.

The drug-induced vasculopathy with nilotinib is thought to be due to pro-atherogenic and anti-angiogenic effects, he said (Hadzijusufovic et al: ASH 2013 Annual Meeting, Abstract 257). And ponatinib has been associated with arterial and venous thrombosis and occlusions, which have occurred in at least 27 percent of all ponatinib clinical trial patients.

“This is very unfortunate—large numbers of patients refractory to second-generation TKIs respond beautifully to ponatinib,” he said, noting that he treats many patients with the drug. “This is an important drug because after ponatinib is transplant.”

It's important to monitor response in patients using the TKIs, he said, also adding that he follows patients for cytogenetic and then molecular response, switching if responses are not adequate, using Europe LeukemiaNet guidelines.

“With only occasional exceptions, the management of CML chronic phase is a marathon, not a sprint,” he said.